Anastrozole, chemically (2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropionitrile) of the formula (1)
is a pharmaceutically active agent acting as a selective nonsteroidal aromatase inhibitor. Aromatase is an enzyme which regulates the level of certain female sex hormones, such as estrogens.
In pharmaceutical applications, anastrozole is used for the treatment of advanced breast cancer in post-menopausal women. In the pharmaceutical compositions it is used in the form of the free base.
The whole class of 1,3-substituted aralkyl heterocyclic compounds, among which the anastrozole compound was a specific example, as well as acid addition salts of these compounds such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate and toluene-p-sulfonate (these salts having not been exemplified in case of anastrozole), have been disclosed in U.S. Pat. No. 4,935,437 (reissued as US RE 36,617) and the EPB 296749.
There are various processes known for the synthesis of the anastrozole. The most important of them use the 1,2,4-triazole as it is a cheap and useful reagent. In the original document, U.S. Pat. No. 4,935,437, the anastrozole compound itself was actually prepared by two such procedures.
The first procedure (see Example 1 of EPB 296749) comprises, in the last steps, a reaction of the methyl compound of the formula (2) with N-bromosuccinimide to yield the bromomethyl-compound of the formula (3), which was treated with sodium 1,2,4-triazole to give the crude anastrozole.

Crude anastrozole was purified by column chromatography (details not given) and crystallization from cyclohexane/ethyl acetate got a purified material with a melting point of 81-82° C. Neither the yield nor the purity is mentioned in the process description. In a later document WO 2005-105762, it is reported that this process was repeated with a poor yield (<50%) and poor quality (<90% by HPLC). In particular, the crystallization procedure was not successful in reducing the level of the isomeric impurity—the isoanastrozole of the formula (4),
which was still contained in a level of more than 1.0% by HPLC.
In a second procedure disclosed in the EPB'749 (Example 8), the last steps use the hydroxymethyl-compound of formula (5), which was converted into a chloromethyl-compound of formula (6). The crude compound (6) (obtained by evaporation of the ethyl acetate extract of the reaction mixture) was reacted with 1,2,4-triazole for 18 hours at the reflux in acetonitrile to yield a mixture of anastrozole and the isoanastrozole of the formula (4). This mixture was separated by column chromatography using methanol-chloroform mixture as the eluent. Also, the yield and the purity of the anastrozole product was not mentioned.

The need to use chromatographic separation makes these processes economically unattractive for industrial scale.
One way to avoid this problem is to use a different synthetic scheme; one that does not produce the isoanastrozole compound and/or produces impurities that are easy to remove. Some regioselective schemes are known; see for example EPB '749 example 69 and WO 2006-000836, which essentially avoid the production of isoanastrozole. But these schemes have disadvantages including the use of expensive and/or toxic reagents and conditions or the requirement of extra synthetic steps. Improving the 1,2,4-triazole process would thus be desirable.
Two later documents were published dealing with attempts to improve the above 1,2,4-triazole-employing process, and in particular with attempts to provide a pharmaceutical grade anastrozole (which is a compound having at least 99.7% purity with max. 0.1% of any single impurity) without the need of a chromatographic purification of the crude anastrozole.
WO 2005-105762 indicates that the known process provides a product with 3-5% of the isoanastrozole impurity (4) when performing the process on an industrial scale. The level of the impurity may be reduced by using dimethyl formamide (“DMF”), advantageously in combination with a non-polar solvent in the coupling reaction. But, the isoanastrozole impurity cannot be removed to <0.1% level by any crystallization technique, even after a repeated crystallization. However, such impurity may be reduced to the <0.1% level by crystallizing an anastrozole salt. After the purification, the required base of anastrozole is obtained by neutralization of the salt.
The overall process of WO 2005-105762 can be summarized as follows:                reacting the bromo-compound (3) with sodium or potassium 1,2,4-triazole in DMF with or without a non-polar solvent;        quenching the reaction mixture with water medium and extracting crude anastrozole with an organic solvent;        distilling the organic solvent and treating the rest with organic or mineral acid to form the acid addition salt of anastrozole;        recrystallizing the acid addition salt from an organic solvent;        neutralization of the salt with a base to obtain anastrozole; and        crystallizing the anastrozole from an organic solvent to get a product of pharmaceutically acceptable grade.        
US 2006-0035950 reports a similar process for the purification of crude anastrozole. The process employs the bromide intermediate (3) as a starting material and has the following characteristics:                the intermediate (3) is preferably purified before its use in the synthesis by crystallization or precipitation;        the coupling of (3) with the sodium 1,2,4-triazole or with the 1,2,4-triazole under basic conditions yielding crude anastrozole is performed in a solvent of the Class 3 or Class 2 (as defined in the Industrial guideline of residual solvents published by the International Conference of Harmonization); and        the crude anastrozole is purified via an isolated anastrozole salt form involving crystallization, acidic extraction, or both.        
The isolated salt form of anastrozole, e.g., as the hydrochloride or hydrobromide salt, is crystallized from an organic solvent or mixtures of the organic solvents (similarly as in WO 2005-105762). The purified salt is then converted back to the desired anastrozole base by neutralization. In the examples, the neutralization is achieved by adding an aqueous solution of an inorganic base (sodium carbonate) and the liberated anastrozole base is extracted into an organic solvent (e.g. toluene) and crystallized therefrom.
Although this crystallization removes most of the impurities, particularly hydrophobic impurities, the published application reports that the isoanastrozole impurity is not sufficiently reduced. In fact, various solvents employed for the crystallization of the anastrozole hydrochloride provided a product having from 1.1 to 8.1% of isoanastrozole. To overcome this, the published application proposes selectively extracting impurities, especially the isoanastrozole, via an acidic solution.
Specifically, a crude anastrozole (base) in an organic solvent is mixed with an aqueous acid solution having a pH between 0.7 to 1.7, whereby the isoanastrozole is selectively removed into the aqueous phase leaving most of the desired anastrozole in the organic phase (however a part of the anastrozole is also removed into the aqueous phase as the reported yield of the single extraction is max. 82%). Upon phase separation and removal of the aqueous phase, the anastrozole-containing organic phase has less isoanastrozole. The extraction may be performed multiple times in order to reach a desired level of isoanastrozole. Contrary to the first process, this process does not efficiently remove hydrophobic impurities.
Therefore, both processes may be advantageously combined: the anastrozole is purified by extraction, then it is converted into the salt, the salt is isolated (whereby it is purified from hydrophobic impurities) and then converted back to the anastrozole base. However, it appears from the examples that multiple acidic extractions are needed in order to adequately reduce the level of isoanastrozole.
In summary, it can be quite difficult to remove impurities from crude anastrozole sufficiently to obtain a pharmaceutically acceptable quality grade. It would be desirable to have an alternative purification process. In particular, a reliable process that can be shorter/simpler and especially cheaper/more efficient would be advantageous.